ABSTRACT Obesity impacts approximately 40% of the adult population in the US, and another 32% are overweight. It is also the major cause of a host of other debilitating diseases, such as type II diabetes mellitus (T2DM). For example, over 90% of T2DM patients are also obese, and the prevalence of T2DM is approximately 21 million in the US alone. Therefore, obesity and T2DM are significant health crises, and given the sub-optimal outcomes of available medications, the development of effective therapies is urgent. Bariatric surgery, including Roux-en-Y gastric bypass (RYGB), has been recognized as an extremely potent and durable treatment for obesity. For example, RYGB leads to approximately 30% weight loss within the first year which is maintained at 21% at ten years. Equally intriguing, RYGB resolves or improves T2DM in approximately 70% of patients. Considering the profound therapeutic effects of RYGB, elucidating the mechanisms by which it improves T2DM and obesity could potentially offer new strategies for developing effective therapeutics. While rigorous research over the past two decades has indicated a myriad of neural, metabolic, and hormonal signals that may mediate the physiological outcomes of the surgery, there is still a lack of mechanistic understanding and consensus as to which mechanisms are responsible for the beneficial effects of RYGB. Our team, and subsequently others, have recently demonstrated that RYGB triggers a profound intestinal metabolic and morphologic remodeling ? that is manifested by significant augmentation of intestinal glucose utilization and hyperplasia. The hallmark of this remodeling is the induction of a GLUT1- and PKM2-mediated hyperactivation of glycolysis and redirection of its byproducts to anabolic pathways, to meet the energetic demand of the rapidly proliferating cells. These observations strongly suggest that RYGB increases glucose demand in the small intestine causing it to assume an active and direct role in the glycemic control following surgery. However, despite these intriguing observations, the potential role of the intestine in the improvement of T2DM is yet unknown. The objective of this proposal is to elucidate the role of the small intestine in the improvement of T2DM post-RYGB, and to shed light on the molecular and cellular mechanisms that underlie the intestinal metabolic and morphologic remodeling. Our approach will be pursued in the following Specific Aims: Aim 1 will determine the causality of the increased intestinal glucose metabolism on glycemic control following RYGB; Aim 2 will elucidate whether increased cellular proliferation underlies the augmented glucose demand; and Aim 3 will determine the key molecular mechanisms underlying the augmented metabolic demand and tissue hyperplasia. Successful achievement of our proposal?s goals is expected to be a detailed understanding of the contribution of the small intestine to amelioration of T2DM following RYGB, as well as the fundamental cellular and molecular mechanisms that underlie the RYGB-induced intestinal metabolic and morphologic remodeling.